The present sequential trial design takes advantage of a window of opportunity to assess PS-341 alone in aggressive large cell lymphomas. However, because recurrent DLBCL is potentially curable with EPOCH chemotherapy alone ( 20%) or stem cell transplant ( 25%), patients who do not enter CR with PS-341 will receive PS-341 and EPOCH chemotherapy. EPOCH chemotherapy was selected because its efficacy has been validated in both recurrent and untreated DLBCL and is a potentially curable regimen. Hence, if PS-341 is shown to be active, it could potentially be combined with EPOCH for the initial treatment of poor prognosis NF-kB-expressing DLBCL. 1.1. Study Objectives Primary 1.1.1 Assess response of PS-341 in diffuse large B-cell lymphoma (DLBCL) and within the ABC and GCB molecular subtypes. 1.1.2 Assess toxicity and safe tolerated dose of PS-341 and EPOCH in DLBCL. 1.1.3 Obtain pilot information on response of PS-341 and EPOCH in DLBCL. Secondary 1.1.4 Assess biological effect of PS-341 on DLBCL tumor biopsies using microarray and IHC, including bcl-2 and NF-kB. 1.1.5 Assess markers of drug resistance (bcl-2, MIB-1, p53) on response to PS-341 and EPOCH.